Treatment of Hypercoagulopathy in Cushing&#39;s Syndrome by Administration of Glucocorticoid Receptor Modulators

ABSTRACT

Novel methods for preventing, reducing the risk of development of, and for treating hypercoagulopathy in Cushing&#39;s syndrome patients with elevated risk of developing hypercoagulopathy are disclosed. The methods are further useful to prevent, to reduce the risk of developing, and to treat deep vein thrombosis (DVT), pulmonary embolism (PE), and venous thromboembolism (VTE); and to treat inflammatory states. 
     The methods include: administering heteroaryl-ketone fused azadecalin glucocorticoid receptor modulator (HKGRM) to a Cushing&#39;s syndrome patient at risk of developing hypercoagulopathy, thereby treating hypercoagulopathy. Methods of preventing, reducing risk of developing, and of treating DVT, PR, or VTE in a Cushing&#39;s syndrome patient comprise administering a HKGRM to the patient. Methods of unmasking and subsequently reducing an inflammatory state comprise administering an effective amount of a HKGRM to a Cushing&#39;s syndrome patient, effective first to increase inflammatory symptoms and then to subsequently decrease said inflammatory symptoms in the patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/723,626, filed Dec. 20, 2019, which claims the benefit of, andpriority to, U.S. Patent Application 62/784,270, filed Dec. 21, 2018,the contents of which are is hereby incorporated by reference in theirentirety.

BACKGROUND

The coagulation of blood is a vital capability required for health,being critical for wound repair, for avoidance of hemorrhage, and forother reasons. Paucity or lack of one or more factors responsible forblood clotting is the cause of hemophilia, a serious inherited disorder.However, blood hypercoagulability (excess propensity of the blood tocoagulate) can lead to significant, and sometimes life-threateningconditions, including intravenous and intraarterial blood clots(thrombi) which may lead to embolisms and strokes (a stroke occurs whenan embolism lodges in the brain vasculature, cutting off blood supply toregions of the brain downstream of the clot). The formation or presenceof a thrombus in the deep veins, typically in the legs, although suchthrombi may form in the upper extremities as well, is termed deep veinthrombosis (DVT). A pulmonary embolism (PE) is caused by an obstructionof a pulmonary artery or branches thereof; such emboli are often causedby thrombi that originally formed in a deep vein. The combination of DVTand PE is termed venous thromboembolism (VTE), and is a seriouscondition. Cushing's syndrome is a disorder in which excessive bloodclotting may be exhibited.

Hypercortisolism, often referred to as Cushing's syndrome, is caused byexcessive activity of the stress hormone cortisol. Where Cushing'ssyndrome is caused by administration of glucocorticoid (GC) drugs, it istermed “exogenous Cushing's syndrome”; cases in which the excesscortisol is produced by the patient are termed “endogenous Cushing'ssyndrome”. Endogenous Cushing's syndrome is often caused by a pituitarytumor (typically an adenoma), and is then termed Cushing's Disease.Cases of endogenous Cushing's syndrome that are caused by non-pituitarysources of cortisol are termed “ectopic Cushing's syndrome”. EndogenousCushing's syndrome is an orphan disease that most often affects adultsaged 20-50. In the United States, an estimated 20,000 patients haveCushing's syndrome, with about 3,000 new patients being diagnosed eachyear. Symptoms vary, but most people experience one or more of thefollowing manifestations: high blood sugar (hyperglycemia), diabetes,high blood pressure, upper-body obesity, rounded face, increased fataround the neck, thinning arms and legs, easy bruising, facial plethora,acne, red purple stripes across the body, severe fatigue and weakmuscles. Irritability, anxiety, cognitive disturbances and depressionare also common. Cushing's syndrome can affect every organ system in thebody and can be lethal if not treated effectively. One cause of death inCushing's syndrome patients is due to emboli caused by hypercoagulopathyassociated with the syndrome. Hypercoagulopathy is associated with, andmay cause, emboli associated with arterial thrombosis or venousthromboembolism (VTE), including pulmonary emboli and deep veinthrombosis. Such emboli may occur and are often fatal. Stroke is anothercommon result of emboli due to hypercoagulopathy.

Cushing's syndrome patients may be treated surgically to remove, as muchas possible, the source of the excess cortisol, and by other means.Cushing's syndrome patients may receive medical treatment, such as byadministration of glucocorticoid receptor modulators, such asmifepristone, to reduce or block the effects of excess cortisol (see,e.g., U.S. Pat. Nos. 9,943,526; 9,956,216, both of which patents arehereby incorporated by reference in their entireties). However, thehypercoagulopathy experienced by Cushing's syndrome patients oftenpersists following surgery for Cushing's syndrome. The coagulationfactors Factor VIII and von Willebrand Factor increased one month aftersurgery, and took six months or more to decline below the levels foundprior to surgery (Casonato, et al. Blood Coagulation and Fibrinolysis10(3):145-151 (1999)).

Accordingly, methods for treating Cushing's syndrome patients in orderto reduce the risk of developing hypercoagulopathy, DVT, PE, VTE, orother embolic disorder are lacking in the art and are required.

SUMMARY

Applicant provides novel methods for preventing or treatinghypercoagulopathy. In embodiments, these novel methods are effective forpreventing or treating hypercoagulopathy in Cushing's syndrome patientsat risk of, or suffering from, a disease or condition associated with anelevated risk of developing hypercoagulopathy, or from a disease orcondition associated with an elevated risk of developing deep veinthrombosis (DVT), pulmonary embolism (PE), and venous thromboembolism(VTE). In embodiments, these novel methods are effective for treating aninflammatory state in Cushing's syndrome patients suffering from adisease or condition associated with an elevated risk of developinghypercoagulopathy, or from a disease or condition associated with anelevated risk of developing DVT, PE, and VTE. In embodiments, thesenovel methods are effective for unmasking an inflammatory state inCushing's syndrome patients suffering from, or at risk of developing,hypercoagulopathy, DVT, PE, or VTE.

In embodiments, the methods comprise prophylactic methods suitable for,and effective for, reducing the risk of development of hypercoagulopathyin Cushing's syndrome patients. In embodiments, the methods compriseprophylactic methods suitable for, and effective for, reducing the riskof development of DVT, PE, and VTE in Cushing's syndrome patients.

In embodiments, Applicant discloses herein methods of treatinghypercoagulopathy in a patient suffering from Cushing's syndrome,comprising: Administering an effective amount of a glucocorticoidreceptor modulator (GRM) to said patient, whereby said hypercoagulopathyis treated. In embodiments, the methods of treating hypercoagulopathy ina patient suffering from Cushing's syndrome further comprise determiningthat the Cushing's syndrome patient is suffers from, or is at elevatedrisk of developing, hypercoagulopathy. In embodiments, the GRM is aglucocorticoid receptor antagonist (GRA). In embodiments, the GRM ismifepristone. In embodiments, the GRM or GRA is a heteroaryl-ketonefused azadecalin GRM (HKGRM). In embodiments, the HKGRM is relacorilant.

In embodiments, Applicant discloses herein methods of reducing the riskof developing DVT, PE, or VTE in a patient suffering from Cushing'ssyndrome, comprising: Administering a medical treatment for Cushing'ssyndrome, said medical treatment comprising administering an effectiveamount of a glucocorticoid receptor modulator (GRM) to said patient,Whereby said risk of developing DVT, PE, or VTE is reduced as comparedto the risk of developing DVT, PE, or VTE in a Cushing's patient who hadnot previously received said medical treatment for Cushing's syndrome.In embodiments, the risk of developing DVT, PE, or VTE in the Cushing'ssyndrome patient is reduced at one month of medical treatment ascompared to the risk, one month following surgery, of developing DVT,PE, or VTE in a Cushing's patient who has received surgical treatmentfor Cushing's syndrome. In embodiments, the methods of reducing the riskof developing DVT, PE, or VTE in a patient suffering from Cushing'ssyndrome further comprise determining that the Cushing's syndromepatient is suffers from, or is at elevated risk of developing,hypercoagulopathy.

In embodiments, Applicant discloses herein methods of unmasking andsubsequently reducing an inflammatory state in a patient suffering fromCushing's syndrome, comprising: Administering an effective amount of aGRM to said patient, Effective to increase inflammatory symptoms in saidpatient within about 4 weeks of beginning said administration, andEffective to subsequently decrease said inflammatory symptoms in saidpatient by about 3 to 4 months after beginning said administration,Whereby said inflammatory state is reduced in Cushing's syndrome. Inembodiments of the methods of unmasking and subsequently reducing aninflammatory state in a patient suffering from Cushing's syndrome, theinflammatory symptoms comprise greater than normal C-Reactive proteinlevels. In embodiments, the methods of unmasking and subsequentlyreducing an inflammatory state in a patient suffering from Cushing'ssyndrome further comprise determining that the Cushing's syndromepatient suffers from, or is at elevated risk of developing,hypercoagulopathy.

In embodiments of the methods disclosed herein, the GRM is a heteroarylketone fused azadecalin GRM, and may be relacorilant. In embodiments ofthe methods disclosed herein, the GRM is a steroidal GRM, and may bemifepristone.

Applicant discloses herein that the coagulation profile of the Cushing'spatients treated with relacorilant was improved compared to baseline. Incontrast to prior observations of Cushing's syndrome patients treatedsurgically, relacorilant administration did not lead to an increase ineither Factor VIII or von Willebrand's Factor, and declined with only afew months of relacorilant treatment. APTT measurements increased inCushing's patients receiving relacorilant, indicating that the risk ofcoagulation and of risk of DVT, PE, and VTE was reduced. These resultsshow that relacorilant treatment improves the coagulation profile ofCushing's patients. These results further suggest that relacorilanttreatment of Cushing's patients provides a better coagulation factorprofile, earlier after treatment, than does surgery.

Accordingly, Applicant provides herein methods to treathypercoagulopathy seen in Cushing's syndrome patients in a way that ismuch safer than surgery. The acute decreases of cortisol activity orcortisol levels associated with successful surgery for Cushing'ssyndrome poses the risk of worsening hypercoagulopathy in thepost-operative period—up to about 4 months—due to the effect ofunderlying inflammation that is suppressed by cortisol excess and flaresupon successful surgery. Gradual treatment of the chronic cortisolexcess, provided by the methods disclosed herein, prevents the acuteexacerbation of occult inflammation and improves the coagulation profilein patients at high risk for DVT, PE, and VTE.

Comparing the coagulation factor changes following successful Cushing'ssyndrome surgery with those in patients treated medically with a GRM itbecomes obvious that the two main coagulation factors associated withsteroid induced hypercoagulaopthy (factor VIII and VWF) are graduallydecreasing with medical treatment, while in patients undergoing surgeryboth of those factors increase post operatively and remain elevated forat least one month post-operative (Casonato, et al. Blood Coagulationand Fibrinolysis 10(3):145-151 (1999)). That also agrees with theobservation of increased risk of DVT, PE, and VTE following successfultreatment of Cushing's syndrome and the Cushing's syndrome treatmentguidelines which recommend use of anti-coagulation for at least 3 monthsfollowing successful surgery. Thus, the present GRM treatments provideadvantages over surgical treatments.

When used as the sole treatment for hypercoagulopathy; or for treatingDVT, PE, or VTE; or for unmasking and treating inflammatory states, thepresent methods are believed to provide better treatments as compared toprevious surgical or medical treatments for the conditions underlyinghypercoagulopathy; risk of DVT, PE, or VTE; and inflammatory states.When used in conjunction with other treatments, the present methods arebelieved to act synergistically with such other treatments to providemore effective treatment for hypercoagulopathy; risk of DVT, PE, or VTE;and inflammatory states than would be provided by the other treatmentsalone. The methods disclosed herein provide advantages of treatinghypercoagulopathy, DVT, PE, VTE, and inflammatory states in a Cushing'ssyndrome patient, either by administration of a GRM alone, or, whenadministered in conjunction with a second anticoagulation therapy, byadding to and improving the prior therapy. The methods disclosed hereinare believed to provide treatments which result in outcomes at least asfavorable as, or better than, outcomes resulting from surgicalprocedures, yet which do not require surgery, and are available topatients unable or unwilling to undergo surgery, or for whom surgeryproved to be incompletely successful or unsuccessful.

Other objects, features, and advantages of the methods disclosed hereinwill be apparent to one of skill in the art from the following detaileddescription and figures.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A shows levels of the coagulation factors Factor VIII and vonWillebrand's Factor over time in Cushing's syndrome patients treatedwith relacorilant. (The vertical scale is shown as %; levels of normalsubjects would be 100.) Factor VIII (darker column at the left of eachpair of columns) and von Willebrand Factor (lighter column at the rightof each pair of columns) are shown at baseline, prior to relacorilantadministration (left-most pair of columns); after four weeks ofrelacorilant treatment (middle pair of columns); and after 3 or 4 monthsof relacorilant treatment (right-most pair of columns). Factor VIIIlevels are reduced, as compared to baseline, at week four and after 3 or4 months of relacorilant treatment. Von Willebrand factor levelsinitially rise somewhat (at four weeks), and then return to baselinelevels after 3 or 4 months of relacorilant treatment.

FIG. 1B shows von Willebrand Factor over time in Cushing's syndromepatients after surgery (top) and during treatment with relacorilant(bottom).

FIG. 1C shows Factor VIII over time in Cushing's syndrome patient aftersurgery (top) and during treatment with relacorilant (bottom). The datain the upper graph showing Factor VIII changes in surgical patients isfrom Casonato et al., 1999. The arrows indicate the upper limit ofnormal levels of Factor VIII.

FIG. 2A shows activated prothrombin time (APTT) measured in Cushing'ssyndrome patients before and after receiving relacorilant. APTT measuredafter up to 16 weeks of relacorilant administration increased in thesepatients as compared to baseline APTT measurements.

FIG. 2B Relacorilant effects on Coagulation: There is a high risk ofthrombotic events in patients with Cushing's syndrome; Cushing'ssyndrome patients treated with relacorilant showed improvement incoagulation factors. This result indicates that relacorilant may beuseful to improve pre-operative coagulation control (before surgery forCushing's syndrome) in Cushing's syndrome patients at high risk ofthrombotic events.

FIG. 3 shows C-Reactive protein levels over time in Cushing's syndromepatients treated with relacorilant. C-Reactive protein level iscorrelated with the level of inflammation in a patient. C-Reactiveprotein levels initially rise somewhat (at four weeks), and then returnto baseline levels after 3 or 4 months of relacorilant treatment. Thesechanges in C-Reactive protein levels are similar to those observed forVon Willebrand factor levels as well.

DETAILED DESCRIPTION

INTRODUCTION

Provided herein are methods for treating a patient at risk forhypercoagulopathy or symptoms and adverse events associated withhypercoagulopathy. In embodiments, the patient at risk forhypercoagulopathy is at risk of developing a deep vein thrombosis (DVT),pulmonary embolism (PE), or a venous thromboembolism (VTE). Inembodiments, the patient at risk for hypercoagulopathy suffers from, oris at risk of developing, an inflammatory state. In embodiments, such apatient at risk for hypercoagulopathy; or at risk of developing DVT, PE,or VTE; or suffering from or at risk of developing an inflammatorystate, is a patient who suffers from Cushing's syndrome. In embodiments,such a Cushing's syndrome patient may suffer from endogenous Cushing'ssyndrome, including ACTH-Dependent Cushing's syndrome; the Cushing'ssyndrome may be pituitary Cushing's syndrome (i.e., Cushing's Disease)and may be ACTH-Independent Cushing's syndrome.

Methods for treating hypercoagulopathy; or DVT, PE, or VTE; orinflammatory states, comprise administration of a glucocorticoidreceptor modulator (GRM). In embodiments, the administration of a GRMcomprises administration of a glucocorticoid receptor antagonist (GRA).In some embodiments, the GRA is a selective inhibitor of theglucocorticoid receptor. In embodiments, the GRM is a nonsteroidal GRMcompound. In embodiments, the GRM is a heteroaryl ketone fusedazadecalin GRM (HKGRM). In embodiments, the HKGRM is relacorilant. Inembodiments, the GRM is a steroidal compound. In embodiments, the GRM ismifepristone.

In embodiments, Applicant discloses a method of treatinghypercoagulopathy in a Cushing's syndrome patient suffering fromhypercoagulopathy, the method comprising:

Administering an effective amount of a glucocorticoid receptor modulator(GRM) to said patient, said GRM administration comprising a firstanticoagulation therapy,

Whereby said hypercoagulopathy is treated. In embodiments, the firstanticoagulation therapy comprises relacorilant administration. Infurther embodiments, a second anticoagulation therapy is administered tothe patient; the second anticoagulation therapy may be administeredbefore, along with, after administration of, or combinations thereof,said first anticoagulation therapy.

In embodiments, Applicant discloses a method of treatinghypercoagulopathy in a Cushing's syndrome patient at elevated risk ofhypercoagulopathy, the method comprising:

Determining that a Cushing's syndrome patient is at elevated risk ofdeveloping hypercoagulopathy,

Administering an effective amount of a glucocorticoid receptor modulator(GRM) to said patient, said GRM administration comprising a firstanticoagulation therapy,

Whereby said hypercoagulopathy is treated. In embodiments, the firstanticoagulation therapy comprises relacorilant administration. Infurther embodiments, a second anticoagulation therapy is administered tothe patient; the second anticoagulation therapy may be administeredbefore, along with, after administration of, or combinations thereof,said first anticoagulation therapy. In embodiments, said elevated riskis determined by one or more of clotting time (where a short clottingtime indicates elevated risk of hypercoagulopathy); levels of bloodclotting factors (where elevated levels of clotting factors (e.g.,Factor VIII, Factor IX, Factor X, von Willibrand factor, and otherclotting factors) indicate elevated risk of hypercoagulopathy); plateletlevels (where elevated platelet levels indicate elevated risk ofhypercoagulopathy); elevated levels of fibrin, fibronectin, D-dimer, andlevels of other fibrin-related molecules indicate elevated risk ofhypercoagulopathy; and presence of a blood clot in the patient indicateselevated risk of hypercoagulopathy.

In embodiments of such methods, the patient suffers from Cushing'ssyndrome, and the method reduced said risk of developinghypercoagulopathy as compared to the risk of developinghypercoagulopathy in a Cushing's syndrome patient who has not receivedsaid first anticoagulation therapy. In embodiments, the patient suffersfrom Cushing's disease. In embodiments, the patient suffers fromACTH-Dependent Cushing's syndrome or ACTH-Independent Cushing'ssyndrome. In embodiments, the patient suffers from ectopic Cushing'ssyndrome.

In embodiments of methods of reducing risk of of developinghypercoagulopathy in a Cushing's syndrome patient, the risk ofdeveloping hypercoagulopathy is reduced at one month of medicaltreatment as compared to the risk, one month following surgery, ofdeveloping hypercoagulopathy in a Cushing's syndrome patient who hasreceived surgical treatment for Cushing's syndrome.

In embodiments, Applicant discloses a method of reducing risk ofdeveloping DVT, PE, or VTE in a patient at risk of developing DVT, PE,or VTE, the method comprising:

Administering an effective amount of a glucocorticoid receptor modulator(GRM) to said Cushing's syndrome patient, said GRM administrationcomprising a first anticoagulation therapy,

Whereby said risk of developing DVT, PE, or VTE is reduced. Inembodiments, the first anticoagulation therapy comprises relacorilantadministration. In further embodiments, a second anticoagulation therapyis administered to the patient; the second anticoagulation therapy maybe administered before, along with, after administration of, orcombinations thereof, said first anticoagulation therapy.

In embodiments of methods of reducing risk of developing DVT, PE, or VTEin a patient at risk of developing DVT, PE, or VTE, the patient suffersfrom Cushing's syndrome, and said risk of developing DVT, PE, or VTE isreduced as compared to the risk of developing DVT, PE, or VTE in aCushing's syndrome patient who has not received said firstanticoagulation therapy. In embodiments, the patient suffers fromCushing's disease. In embodiments, the patient suffers fromACTH-Dependent Cushing's syndrome or ACTH-Independent Cushing'ssyndrome. In embodiments, the patient suffers from ectopic Cushing'ssyndrome.

In embodiments of methods of reducing risk of DVT, PE, or VTE in apatient at risk of developing DVT, PE, or VTE, the risk of developingDVT, PE, or VTE is reduced at one month of medical treatment as comparedto the risk, one month following surgery, of developing DVT, PE, or VTEin a Cushing's syndrome patient who has received surgical treatment forCushing's syndrome.

In embodiments, Applicant discloses a method of method of unmasking andsubsequently reducing an inflammatory state in a patient suffering fromCushing's syndrome, the method comprising:

Administering an effective amount of a glucocorticoid receptor modulator(GRM) to said patient, wherein said effective amount of GRM is effectiveto increase inflammatory symptoms in said patient within about fourweeks of beginning said GRM administration, and

-   -   Is effective to subsequently decrease said inflammatory symptoms        in said patient by about three to about four months after        beginning said GRM administration,    -   Whereby said inflammatory state in said Cushing's syndrome        patient is reduced. In embodiments, the GRM is relacorilant.

In embodiments of methods of unmasking and subsequently reducing aninflammatory state in a patient suffering from Cushing's syndrome,symptoms of said inflammatory state comprise C-reactive protein levelsin said Cushing's syndrome patient that are greater than C-reactiveprotein levels typically found in normal subjects.

In embodiments of the methods disclosed herein, the patient is treatedwith a GRM (e.g., relacorilant) prior to undergoing surgery forCushing's syndrome, effective to reduce risk of hypercoagulopathysubsequent to such surgery. It is believed that administration of a GRM(e.g., relacorilant) according to the methods disclosed herein iseffective to reduce post-operative risk of hypercoagulopathy, forexample, in Cushing's syndrome undergoing surgery. Thus, the methodsdisclosed herein are believed to provide prophylaxis forhypercoagulopathy in Cushing's syndrome; and, in particular embodiments,the methods disclosed herein are believed to provide prophylaxis forhypercoagulopathy in Cushing's syndrome planning or preparing forsurgery; for hypercoagulopathy in Cushing's syndrome undergoing surgery;and for hypercoagulopathy in Cushing's syndrome patients soon aftersurgery (e.g., within a few days following surgery).

In embodiments of any of the methods disclosed herein, a patient isidentified as a patient likely to derive benefit from the methods oftreatment by being identified as having short blood coagulation time,excessive levels of blood coagulation factors (e.g., von Willebrandfactor, Factor VIII, abnormal platelet levels, or other indication ofabnormal blood coagulation indicative of increased risk of a coagulationdisorder).

In embodiments of the methods disclosed herein, the GRM is a GRA. Inembodiments, the GRM is a heteroaryl ketone fused azadecalin GRMcompound (HKGRM). In embodiments, the HKGRM is relacorilant. Inembodiments, the GRM is mifepristone.

In embodiments, the GRM is administered orally to the patient. Inembodiments, the GRM is administered once per day. In embodiments, theGRM is administered twice per day. In embodiments, the GRM isadministered three times per day. In embodiments, the GRM isadministered once every other day. In embodiments, the GRM isadministered once every third day.

HKGRM compounds suitable for use in the methods disclosed hereininclude, without limitation:

-   (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone    (termed “relacorilant”; also termed “CORT125134”), which has the    following structure:

-   (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,-7,    8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone    (termed “CORT122928”), which has the following structure:

and

-   (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl) sulfonyl)-4,    4a, 5,6,7, 8-hexahydro-1-H-pyrazolo P,4-g]isoquinolin-4a-yl)    (pyridin-2-yl)methanone (termed “CORT113176”), which has the    following structure:

In embodiments, the GRM is a heteroaryl ketone fused azadecalin compoundselected from relacorilant, CORT122928, and CORT113176. In embodiments,the dose of HKGRM is administered orally to the patient. In embodiments,the dose of HKGRM is selected from 50 milligrams (mg), 100 mg, 150 mg,200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg,650 mg, and 700 mg. In embodiments, the HKGRM dose is a daily dose. Inembodiments, the HKGRM dose is administered once per day. Inembodiments, the HKGRM is relacorilant.

In embodiments, the GRM is a steroidal compound. In embodiments, the GRMis a glucocorticoid receptor antagonist (GRA). In embodiments, the GRMis mifepristone. In embodiments, the dose of mifepristone isadministered orally to the patient. In embodiments, the dose ofmifepristone is selected from 300 milligrams (mg), 600 mg, 900 mg, and1200 mg. In embodiments, the dose of mifepristone is a daily dose. Inembodiments, the dose of mifepristone is administered once per day.

In embodiments, the patient is administered a second anticoagulationtherapy in addition to the GRM anticoagulation therapy. In embodiments,the second anticoagulation therapy may include, for example,administration of a thrombolytic agent, administration of ananticoagulant, administration of an anti-platelet agent (an agent thatinhibits platelet aggregation), or other agent. In embodiments, thesecond anticoagulation therapy comprises administration of athrombolytic agent selected from tissue plasminogen activator (tPA),streptokinase, and urokinase. In embodiments, the second anticoagulationtherapy comprises administration of an anti-platelet agent selected fromaspirin, clopidogrel, dipyridamole, and abciximab. In embodiments, thesecond anticoagulation therapy comprises administration of a heparin,including low-molecular weight heparin. In embodiments, the secondanticoagulation therapy comprises administration of an agent selectedfrom heparin, warfarin (coumadin), Fondaparinux (Arixtra), rivaroxaban(Xarelto), dabigatran (Pradaxa), apixaban (Eliquis), edoxaban (Savaysa),and enoxaparin (Lovenox). In embodiments, the second anticoagulationtherapy is administered at the same time, or closely in time, to theadministration of the GRM anticoagulation therapy. In embodiments, thesecond anticoagulation therapy is administered at a time after theadministration of the GRM anticoagulation therapy. In embodiments, thetime after said administration of the GRM anticoagulation therapy is atime selected from one hour, two hours, three hours, four hours, fivehours, ten hours, twelve hours, one day, two days, three days, one week,and two weeks. In embodiments, the second anticoagulation therapy isadministered at a time before the administration of the GRManticoagulation therapy. In embodiments, the time before saidadministration of the GRM anticoagulation therapy is a time selectedfrom one hour, two hours, three hours, four hours, five hours, tenhours, twelve hours, one day, two days, three days, one week, and twoweeks.

In embodiments, the methods disclosed herein may be directed to thetreatment of a patient not otherwise in need of treatment with a GRM ora GRA. Such a patient “not otherwise in need of treatment with a GRM ora GRA” is a patient not suffering from a condition known in the art tobe effectively treatable with a GRM or a GRA. Conditions known in theart to be effectively treatable with a GRM or GRA can include, but arenot limited to: drug withdrawal, psychosis, dementia, stress disorders,and psychotic major depression. Thus, in embodiments, the presentmethods are directed to patients not otherwise in need of, or notreceiving, treatment with a GRM or a GRA.

Applicant discloses herein that relacorilant treatment is at least aseffective as surgery (to remove a tumor or tumors causing excesscortisol levels) in terms of the improvement in hypercoagulopathy inCushing's syndrome patients. A study of changes in Factor VIII levels inCushing's patients treated with surgery determined that Factor VIIIlevels initially rose following surgery, showing worsening levels ofFactor VIII at one month following surgical treatment (Casonato, et al.Blood Coagulation and Fibrinolysis 10(3):145-151 (1999)). As shown inFIG. 1 , Factor VIII levels in Cushing's syndrome patients treated withrelacorilant showed a gradual decline to normal range of Factor VIIIlevels without surgery. These results show more favorable changes infactor VIII levels with medical treatment (relacorilant administration)as compared to changes in factor VIII levels following surgery(worsening levels at one month following surgical treatment). Thus, thecoagulation profile observed in Cushing's syndrome patients treated withrelacorilant was better than the coagulation profile observed inCushing's syndrome patients treated with surgery. Relacorilant also hasthe advantage of not raising cortisol and not increasing the risk ofhypokalemia (see U.S. Patent Application 62/783,015, filed Dec. 20,2018, hereby incorporated by reference in its entirety).

The DVT, PE, and VTE outcomes observed in Cushing's syndrome patientstreated with relacorilant as compared to DVT, PE, and VTE outcomesobserved in Cushing's syndrome patients treated with surgery areconsistent with the results shown in FIG. 1 for coagulation factors. Nothromboembolic events were observed in the clinical study of 35Cushing's syndrome patients treated with relacorilant, while in thepublished surgical series the VTE rates were high in patients nottreated with anti-coagulants.

As noted above, factor VIII levels improved at week 4 and normalized atthe end of the study (3^(rd) or 4^(th) month) in patients treated withrelacorilant. Applicant notes that the changes observed in the levels ofvon Willebrand factor observed in Cushing's syndrome patients treatedwith relacorilant (see FIG. 1 ) were similar to those that have beenobserved in Cushing's syndrome patients treated with surgery. Thus, VonWillebrand factor levels followed the same trend as was observed inpatients with successful surgery: Von Willebrand factor levels increasedimmediately following surgery, and started coming down 3 months aftersurgery.

Without being bound by theory, Applicant notes that Von Willebrandfactor is elevated in patients with inflammatory conditions, and furthernotes that glucocorticoids decrease Von Willebrand factor levels. Thetemporal trend of C-Reactive Protein (an inflammation marker) is similarto that of Von Willebrand factor levels in Cushing's patients treatedwith relacorilant. Thus, it appears that GRM treatment unmasks anunderlying inflammatory state; such an underlying inflammatory state waschronically suppressed by the cortisol excess in Cushing's syndromepatients. GRM (e.g., relacorilant) treatment relieves the effects ofsuch cortisol excess, thereby unmasking the underlying inflammatorystate, and then, over time, reducing that inflammation (seen by thesubsequent decrease in C-Reactive Protein by the 3^(rd) or 4^(th) monthafter beginning GRM treatment). Thus, the changes in C-Reactive Proteinlevels correlate closely with the changes we observed in von WillebrandFactor levels. In addition, these changes provide further additionalpharmacodynamic evidence of the GR antagonistic effects of relacorilanttreatment.

I. Definitions

The terms “a,” “an,” or “the” as used herein not only include aspectswith one member, but also include aspects with more than one member. Forinstance, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a cell” includes a plurality of such cells andreference to “the agent” includes reference to one or more agents knownto those skilled in the art, and so forth.

The term “pituitary tumor” as used herein includes, but is not limitedto, lactotrophic adenoma or prolactinoma, ACTH-secreting adenoma,somatotrophic adenomas, corticotrophic adenoma, gonadotrophic adenoma,thyrotrophic adenomas, and null cell adenoma. An ACTH-secretingpituitary tumor may be found in the anterior lobe of the pituitary,usually measuring less than about 5 mm in diameter. Most pituitaryACTH-secreting adenomas (about 90%) are small in size (i.e.,microadenomas).

The term “Cushing's syndrome” refers to a disease caused by prolongedexposure to endogenous or exogenous glucocorticoids. Cushing's syndromepatients often suffer hyperglycemia secondary to hypercortisolism.Symptoms of Cushing's syndrome include, but are not limited to one ormore of the following: hyperglycemia, high blood pressure, weight gain,poor short term memory, poor concentration, irritability, excess hairgrowth, impaired immunological function, ruddy complexion, extra fat inthe neck region, moon face, fatigue, red stretch marks, irregularmenstruation, or a combination thereof. Symptoms of Cushing's syndromecan additionally or alternatively include without limitation one or moreof the following: insomnia, recurrent infection, thin skin, easybruising, weak bones, acne, balding, depression, hip or shoulderweakness, swelling of the extremities, diabetes mellitus, elevated whiteblood cell count, hypokalemic metabolic alkalosis, or a combinationthereof.

The term “endogenous Cushing's syndrome” refers to a type of Cushing'ssyndrome caused by endogenous overproduction of cortisol by the patient,typically due to a pituitary ACTH-secreting tumor (Cushing's disease), anon-pituitary ACTH-secreting tumor, or a cortisol-secreting tumor(adrenal or extra-adrenal). ACTH-secreting tumors can be, e.g.,pituitary adenomas, pituitary adenocarcinomas, carincinoid tumors,neuroendocrine tumors, or other tumors. Cortisol-secreting tumorsinclude, and are not limited to, cortisol producing adrenal adenomas,adrenocortical carcinomas, primary pigmented micronodular adrenaldisease (PPNAD), ACTH independent macronodular adrenal hyperplasia(AIMAH), and extra-adrenal cortisol secreting tumors, e.g., ovariancarcinomas.

“Patient” and “subject” are used interchangeably to refer to a humansubject who may be in need of treatment for Cushing's syndrome. In somecases, the patient may be in need of treatment for Cushing's Disease.

The term “administering” includes oral administration, topical contact,administration as a suppository, intravenous, intraperitoneal,intramuscular, intralesional, intrathecal, intranasal, or subcutaneousadministration, or the implantation of a slow-release device, e.g., amini-osmotic pump, to a subject. Administration is by any route,including parenteral and transmucosal (e.g., buccal, sublingual,palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteraladministration includes, e.g., intravenous, intramuscular,intra-arteriole, intradermal, epicutaneous, subcutaneous,intraperitoneal, intraventricular, and intracranial. Other modes ofdelivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc.

The term “sample” refers to a biological sample obtained from a humansubject. Such samples are typically removed from the subject, and, whenobtained, become entirely separate from the subject (i.e., are in vitrosamples). The sample can be any cell, tissue or fluid sample obtainedfrom a human subject. The sample may be, e.g., a blood sample, a salivasample, a urine sample, or other sample obtained from the patient.Samples can be subject to various treatment, storage or processingprocedures before being analyzed according to the methods describedherein. Generally, the terms “sample” or “samples” are not intended tobe limited by their source, origin, manner of procurement, treatment,processing, storage or analysis, or any modification. Thus, inembodiments, samples are in vitro samples and may be analyzed using invitro methods. The methods disclosed herein are in vitro methods whenused with samples obtained from, and removed from, the human subject.

The term “adrenocorticotropic hormone” or “ACTH” refers to apolypeptide-based hormone that is normally produced and secreted by theanterior pituitary gland. ACTH stimulates secretion of cortisol andother glucocorticoids (GCs) by specialized cells of the adrenal cortex.In healthy mammals, ACTH secretion is tightly regulated. ACTH secretionis positively regulated by corticotropin releasing hormone (CRH), whichis released by the hypothalamus. ACTH secretion is negatively regulatedby cortisol and other glucocorticoids. A disruption to the tightlyregulated hypothalamus-pituitary-adrenal gland (HPA) axis can cause lowlevels of ACTH and cortisol, and in turn, secondary adrenalinsufficiency.

The term “glucocorticoid” (“GC”) includes any compound known in the artthat is referred to as a glucocorticoid receptor agonist,glucocorticoid, glucocorticosteroid, corticoid, corticosteroid, orsteroid that binds to and activates a glucocorticoid receptor.“Glucocorticosteroid” refers to a steroid hormone or steroidal moleculethat binds to the glucocorticoid receptor. Glucocorticosteroids are GCs.Glucocorticosteroids are typically characterized by having 21 carbonatoms, an α,β-unsaturated ketone in ring A, and an α-ketol groupattached to ring D. They differ in the extent of oxygenation orhydroxylation at C-11, C-17 and C-19 (Rawn, “Biosynthesis and Transportof Membrane Lipids and Formation of Cholesterol Derivatives,” inBiochemistry, Daisy et al. (eds.), 1989, pg. 567).

As used herein, the term “cortisol” refers to the naturally occurringglucocorticoid hormone (also known as hydrocortisone) having thestructure:

Cortisol is a glucocorticoid hormone that is produced by the zonafasciculata of the adrenal gland. The term “total cortisol” refers tocortisol that is bound to cortisol-binding globulin (CBG or transcortin)and free cortisol (cortisol that is not bound to CBG). The term “freecortisol” refers to cortisol that is not bound to cortisol-bindingglobulin (CBG or transcortin). As used herein, the term “cortisol”refers to total cortisol, free cortisol, and/or cortisol bound to CBG.

“Glucocorticoid receptor” (“GR”) refers to the type II GR whichspecifically binds to cortisol and/or cortisol analogs such asdexamethasone (See, e.g., Turner & Muller, J Mol Endocrinol, 2005 35283-292). The GR is also referred to as the cortisol receptor. The termincludes isoforms of GR, recombinant GR and mutated GR. Inhibitionconstants (K_(i)) against the human GR receptor type II (Genbank:P04150) are between 0.0001 nM to 1,000 nM; preferably between 0.0005 nMto 10 nM, and most preferably between 0.001 nM to 1 nM.

The term “glucocorticoid receptor modulator” or “GRM” refers to anycomposition or compound which changes (“modulates”) the binding of aglucocorticoid receptor (GR) agonist, such as cortisol, or cortisolanalogs, synthetic or natural, to a GR, or which changes (“modulates”)the activity of a GR resulting from GR agonist binding. Thus, a GRMalters the effect of GR agonist binding that would occur in the absenceof the GRM.

The term “glucocorticoid receptor antagonist” or “GRA” refers to a GRMwhich partially or completely inhibits (antagonizes) the binding of aglucocorticoid receptor (GR) agonist, such as cortisol, or cortisolanalogs, synthetic or natural, to a GR. A GRA is a GRM which providesantagonistic modulation of the effect of GR agonist binding that wouldoccur in the absence of the GRA. A “specific glucocorticoid receptorantagonist” refers to any composition or compound which inhibits anybiological response associated with the binding of a GR to an agonist.By “specific,” the drug preferentially binds to the GR rather than othernuclear receptors, such as mineralocorticoid receptor (MR), androgenreceptor (AR), or progesterone receptor (PR). It is preferred that thespecific glucocorticoid receptor antagonist bind GR with an affinitythat is 10× greater ( 1/10^(th) the K_(d) value) than its affinity tothe MR, AR, or PR, both the MR and PR, both the MR and AR, both the ARand PR, or to the MR, AR, and PR. In a more preferred embodiment, thespecific glucocorticoid receptor antagonist binds GR with an affinitythat is 100× greater ( 1/100^(th) the K_(d) value) than its affinity tothe MR, AR, or PR, both the MR and PR, both the MR and AR, both the ARand PR, or to the MR, AR, and PR.

The term “selective inhibitor” in the context of glucocorticoidreceptor, refers to a chemical compound that selectively interferes withthe binding of a specific glucocorticoid receptor agonist and theglucocorticoid receptor.

The term “steroidal backbone” in the context of glucocorticoid receptorantagonists containing such refers to glucocorticoid receptorantagonists that contain modifications of the basic structure ofcortisol, an endogenous steroidal glucocorticoid receptor ligand. Thebasic structure of a steroidal backbone is provided as Formula I:

The two most commonly known classes of structural modifications of thecortisol steroid backbone to create glucocorticoid antagonists includemodifications of the 11-β hydroxy group and modification of the 17-βside chain (See, e. g., Lefebvre (1989) J. Steroid Biochem. 33:557-563).

As used herein, the term “mifepristone” refers to11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-propynyl)-estra-4,9-dien-3-one),also referred to as RU486, or as RU38.486, or as17-beta-hydroxy-11-beta-(4-dimethyl-aminophenyl)-17-alpha-(1-propynyl)-estra-4,9-dien-3-one).Mifepristone binds to the glucocorticoid receptor (GR), typically withhigh affinity, and inhibits the biological effects initiated/mediated bythe binding of any cortisol or cortisol analogue to a GR receptor.Salts, hydrates and prodrugs of mifepristone are all included in theterm “mifepristone” as used herein. Thus, used herein, “mifepristone”refers to the molecule that has the following structure:

and to salts, hydrates and prodrugs thereof, and pharmaceuticalcompositions thereof.

As used herein, the phrase “non-steroidal backbone” in the context ofglucocorticoid receptor antagonists containing such refers toglucocorticoid receptor antagonists that do not share structuralhomology to, or are not modifications of, cortisol. Such compoundsinclude synthetic mimetics and analogs of proteins, including partiallypeptidic, pseudopeptidic and non-peptidic molecular entities.

Non-steroidal GRM compounds also include glucocorticoid receptorantagonists having a heteroaryl ketone fused azadecalin backbone.Exemplary GRMs having a heteroaryl ketone fused azadecalin backboneinclude those described in U.S. Pat. Nos. 8,859,774; 9,273,047; and9,707,223. All patents, patent publications, and published articlescited herein, both supra and infra, are hereby incorporated by referencein their entireties, including all compounds and compositions disclosedin the patents, patent publications, and published articles citedherein.

As used herein, the term “relacorilant” refers to the heteroaryl ketonefused azadecalin compound(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone(Example 18 of U.S. Pat. No. 8,859,774), which has the followingstructure:

As used herein, the term “CORT122928” refers to the heteroaryl ketonefused azadecalin compound(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,-7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone(Example 1C of U.S. Pat. No. 8,859,774), which has the followingstructure:

As used herein, the term “CORT113176” refers to the heteroaryl ketonefused azadecalin compound(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl) sulfonyl)-4, 4a,5,6,7,8-hexahydro-1-H-pyrazolo P,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (Example 1 of U.S. Pat. No. 8,859,774) which hasthe following structure:

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors and colors, and the like. One of skill in the art will recognizethat other pharmaceutical excipients are useful in the presentinvention.

Methods of Diagnosis and Treatment

Cushing's syndrome may be diagnosed without knowledge of the source ofthe excess cortisol or GC action which characterizes the syndrome. Thus,while treatment (e.g., administration of a GRM such as mifepristone) maybegin, further diagnostic information may need to be acquired in orderto provide the patient with the best treatment for their condition. Thepresent methods provide GRM treatment of Cushing's syndrome and at thesame time that treatment is effective to treat conditions associatedwith Cushing's syndrome, such as hypercoagulopathy; DVT, PE, and VTE;and inflammatory states in the patient.

The methods may include obtaining biological samples from a patientsuffering from Cushing's syndrome. The biological sample can be saliva,urine, whole blood, plasma, serum, or another biological sample from thepatient. In some embodiments, the biological sample is a blood sample.In embodiments, detection or measurements of factors of the intrinsicpathway of blood clotting are performed using such a sample; inembodiments, detection or measurements of factors of the extrinsicpathway (also termed the tissue factor pathway) of blood clotting areperformed using such a sample. In embodiments, coagulation parameters(such as, e.g., clotting time), or platelets, or levels of coagulationfactors (such as, e.g., Factor VIII, von Willebrand's factor, factor IX,factor X, factor XI, factor XII (Hageman factor), factor XIII, fibrin,fibrinogen, thrombin, prothrombin, plasma thrombolastin antecedent,Stuart factor, etc.) are determined from a blood sample obtained fromthe patient. In embodiments, markers or factors indicative ofinflammation and of the presence, extent, or absence of an inflammatorystate in the patient (such as, e.g., erythrocyte sedimentation rate, andlevels of C-Reactive Protein, procalcitonin, eosinophil counts, plateletcounts, cytokine levels (e.g., levels of interleukin-6, tumor necrosisfactor, adiponectin, monocyte chemoattractant protein 1 (MCP-1), CD40ligand, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)),fibrinogen, ferritin, etc.) are determined from a blood sample obtainedfrom the patient.

Normal ranges of some of such coagulation factors and inflammationmarkers include: APTT: 22-34 seconds; von Willibrand Factor: 50-217%;Factor VIII: 50-180%; Factor IX: 60-160%; Factor X: 70-150%; D-Dimer:less than or equal to 0.4999 μg/mL; plasma fibrinogen: 2-4 g/L;thrombin-antithrombin: less than or equal to 3.99 μg/L; osteocalcin:8-37 UG/L; C-reactive Protein: less than or equal to 3.099 μg/L;platelet count: 130,000-400,000 cells per cubic millimeter; eosinophils:0.05-0.55 thousands per μL (or, as percent—eosinophils: 0-7% of whiteblood cells).

Hypercoagulopathy may be diagnosed by blood test, including measurementof blood clotting time, fibrin degradation products (e.g., d-dimertest), erythrocyte sedimentation rate (or other blood viscosity test),and clotting parameters (e.g., measuring platelets, measuring APTT(activated prothrombin time, also known as activated partialthromboplastin time (aPTT)), or by other suitable test); by physicalexamination of the patient to detect a blood clot, by imaging (e.g.,ultrasound or other suitable imaging) to detect a blood clot, or byother means. Coagulation markers which may be measured and tracked usingblood tests include, for example, Factor VIII, von Willebrand Factor,platelet counts, activated partial thromboplastin time (aPTT), Factor V,Factor X, thrombin-antithrombin, and other factors. Blood clotting timemay be measured by, e.g., APTT or other test.

Deep vein thrombosis (DVT), pulmonary embolism (PE), VenousThromboembolism (VTE), and other such thrombotic disorders may bediagnosed by physical examination of the patient; by blood test (e.g.,d-dimer test for the presence of fibrin degradation products, or byother suitable test), platelet counts and other blood tests; by imaging(e.g., ultrasound CT scan, MRI, or other suitable imaging); or by othersuitable means.

The presence of an inflammatory state may be diagnosed by physicalexamination of the patient; observation of accumulation of monocytes,mast cells, T-cells, or other blood cells; by blood test for levels ofinflammatory factors, such as, e.g., cytokines, chemokines,interleukins, histamine, prostaglandins, C-reactive protein, tumornecrosis factor, and others.

Glucocorticoid Receptor Antagonists

The methods of the present invention generally provide administering aglucocorticoid receptor modulator (GRM), which may be a glucocorticoidreceptor antagonist (GRA). In some cases, the GRM is a specific GRM. Asused herein, a specific GRM refers to a composition or compound whichmodulates any biological response associated with the binding of aglucocorticoid receptor (GR) to an agonist by preferentially binding tothe GR rather than another nuclear receptor (NR). In some cases, the GRAis a specific GRA. As used herein, a specific GRA refers to acomposition or compound which inhibits any biological responseassociated with the binding of a GR to an agonist by preferentiallybinding to the GR rather than another nuclear receptor (NR). In someembodiments, the specific GRM binds preferentially to GR rather than themineralocorticoid receptor (MR), androgen receptor (AR), or progesteronereceptor (PR). In an exemplary embodiment, the specific GRM bindspreferentially to glucocorticoid receptor rather than themineralocorticoid receptor (MR). In another exemplary embodiment, thespecific GRM binds preferentially to GR rather than the progesteronereceptor (PR). In another exemplary embodiment, the specific GRM bindspreferentially to glucocorticoid receptor rather than the androgenreceptor (AR). In yet another exemplary embodiment, the specific GRMbinds preferentially to glucocorticoid receptor in comparison to MR andPR, MR and AR, PR and AR, or MR, PR, and AR.

Synthetic 11-beta phenyl-aminodimethyl steroids include mifepristone,also known as RU486, or 17-β-hydrox-11-β-(4-dimethyl-aminophenyl)17-α-(1-propynyl)estra-4,9-dien-3-one). Mifepristone has been shown tobe a powerful antagonist of both the progesterone and glucocorticoid(GR) receptors. Thus, in some embodiments, the GRM is mifepristone. Suchtreatments may be useful in treating hypercoagulopathy, VTE, andinflammatory states associated with Cushing's syndrome.

Non-Steroidal Anti-Glucocorticoids as Glucocorticoid Receptor Modulators

Non-steroidal GRMs are also used in the methods of the invention totreat hypercoagulopathy, VTE, and inflammatory states in a subject. Insome embodiments, hypercoagulopathy, VTE, and inflammatory states may betreated with an effective amount of a non-steroidal GRM having aheteroaryl ketone fused azadecalin backbone. For example,hypercoagulopathy, VTE, and inflammatory states can be treated witheffective amounts of one of the foregoing GRMs. Exemplary GRMs having aheteroaryl ketone fused azadecalin backbone include those described inU.S. Pat. No. 8,859,774.

Pharmaceutical Compositions of Glucocorticoid Receptor Modulators

The GRM administered in the practice of the methods disclosed herein canbe prepared in any suitable form, including in a wide variety of oral,parenteral and topical dosage forms. Oral preparations of either includetablets, pills, powder, dragees, capsules, liquids, lozenges, cachets,gels, syrups, slurries, suspensions, etc., suitable for ingestion by thepatient. The GRA compositions of the present invention can also beadministered by injection, that is, intravenously, intramuscularly,intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.Also, the GRM compositions described herein can be administered byinhalation, for example, intranasally. Additionally, the GRMcompositions of the present invention can be administered transdermally.The GRM compositions of this invention can also be administered byintraocular, intravaginal, and intrarectal routes includingsuppositories, insufflation, powders and aerosol formulations (forexamples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol.35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111,1995). Accordingly, the present invention provides pharmaceuticalcompositions of a GRM including a pharmaceutically acceptable carrier orexcipient and a GRM compound as disclosed herein.

For preparing pharmaceutical compositions from the GRM compound asdisclosed herein, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances, which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material. Details ontechniques for formulation and administration are well described in thescientific and patent literature, see, e.g., the latest edition ofRemington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa.(“Remington's”).

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5% or 10% to70% of the compounds of the present invention.

Suitable solid excipients include, but are not limited to, magnesiumcarbonate; magnesium stearate; talc; pectin; dextrin; starch;tragacanth; a low melting wax; cocoa butter; carbohydrates; sugarsincluding, but not limited to, lactose, sucrose, mannitol, or sorbitol,starch from corn, wheat, rice, potato, or other plants; cellulose suchas methyl cellulose, hydroxypropylmethyl-cellulose, or sodiumcarboxymethylcellulose; and gums including arabic and tragacanth; aswell as proteins including, but not limited to, gelatin and collagen. Ifdesired, disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Dragee cores are provided with suitable coatings such as concentratedsugar solutions, which may also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for product identification or to characterize the quantity ofactive compound (i.e., dosage). Pharmaceutical preparations of theinvention can also be used orally using, for example, push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and acoating such as glycerol or sorbitol. Push-fit capsules can contain thecompounds of the present invention mixed with a filler or binders suchas lactose or starches, lubricants such as talc or magnesium stearate,and, optionally, stabilizers. In soft capsules, the compounds of thepresent invention may be dissolved or suspended in suitable liquids,such as fatty oils, liquid paraffin, or liquid polyethylene glycol withor without stabilizers.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the compoundsof the present invention are dispersed homogeneously therein, as bystirring. The molten homogeneous mixture is then poured into convenientsized molds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingone or more compounds of the present invention in water and addingsuitable colorants, flavors, stabilizers, and thickening agents asdesired. Aqueous suspensions suitable for oral use can be made bydispersing the finely divided active component in water with viscousmaterial, such as natural or synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodiumalginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, anddispersing or wetting agents such as a naturally occurring phosphatide(e.g., lecithin), a condensation product of an alkylene oxide with afatty acid (e.g., polyoxyethylene stearate), a condensation product ofethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethylene oxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol (e.g.,polyoxyethylene sorbitol mono-oleate), or a condensation product ofethylene oxide with a partial ester derived from fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Oil suspensions can be formulated by suspending the compounds of thepresent invention in a vegetable oil, such as arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin;or a mixture of these. The oil suspensions can contain a thickeningagent, such as beeswax, hard paraffin or cetyl alcohol. Sweeteningagents can be added to provide a palatable oral preparation, such asglycerol, sorbitol or sucrose. These formulations can be preserved bythe addition of an antioxidant such as ascorbic acid. As an example ofan injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther.281:93-102, 1997. The pharmaceutical formulations of the invention canalso be in the form of oil-in-water emulsions. The oily phase can be avegetable oil or a mineral oil, described above, or a mixture of these.Suitable emulsifying agents include naturally-occurring gums, such asgum acacia and gum tragacanth, naturally occurring phosphatides, such assoybean lecithin, esters or partial esters derived from fatty acids andhexitol anhydrides, such as sorbitan mono-oleate, and condensationproducts of these partial esters with ethylene oxide, such aspolyoxyethylene sorbitan mono-oleate. The emulsion can also containsweetening agents and flavoring agents, as in the formulation of syrupsand elixirs. Such formulations can also contain a demulcent, apreservative, or a coloring agent.

The GRM compositions provided herein can also be delivered asmicrospheres for slow release in the body. For example, microspheres canbe formulated for administration via intradermal injection ofdrug-containing microspheres, which slowly release subcutaneously (seeRao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable andinjectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863,1995); or, as microspheres for oral administration (see, e.g., Eyles, J.Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermalroutes afford constant delivery for weeks or months.

In another embodiment, the GRM compositions of the present invention canbe formulated for parenteral administration, such as intravenous (IV)administration or administration into a body cavity or lumen of anorgan. The formulations for administration will commonly comprise asolution of the compositions of the present invention dissolved in apharmaceutically acceptable carrier. Among the acceptable vehicles andsolvents that can be employed are water and Ringer's solution, anisotonic sodium chloride. In addition, sterile fixed oils canconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid can likewisebe used in the preparation of injectables. These solutions are sterileand generally free of undesirable matter. These GRM formulations may besterilized by conventional, well known sterilization techniques. Theformulations may contain pharmaceutically acceptable auxiliarysubstances as required to approximate physiological conditions such aspH adjusting and buffering agents, toxicity adjusting agents, e.g.,sodium acetate, sodium chloride, potassium chloride, calcium chloride,sodium lactate and the like. The concentration of the compositions ofthe present invention in these formulations can vary widely, and will beselected primarily based on fluid volumes, viscosities, body weight, andthe like, in accordance with the particular mode of administrationselected and the patient's needs. For IV administration, the GRMformulation can be a sterile injectable preparation, such as a sterileinjectable aqueous or oleaginous suspension. This suspension can beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationcan also be a sterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of1,3-butanediol.

In another embodiment, the formulations of the compositions of thepresent invention can be delivered by the use of liposomes which fusewith the cellular membrane or are endocytosed, i.e., by employingligands attached to the liposome, or attached directly to theoligonucleotide, that bind to surface membrane protein receptors of thecell resulting in endocytosis. By using liposomes, particularly wherethe liposome surface carries ligands specific for target cells, or areotherwise preferentially directed to a specific organ, one can focus thedelivery of the compositions of the present invention into the targetcells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306,1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J.Hosp. Pharm. 46:1576-1587, 1989).

Lipid-based drug delivery systems include lipid solutions, lipidemulsions, lipid dispersions, self-emulsifying drug delivery systems(SEDDS) and self-microemulsifying drug delivery systems (SMEDDS). Inparticular, SEDDS and SMEDDS are isotropic mixtures of lipids,surfactants and co-surfactants that can disperse spontaneously inaqueous media and form fine emulsions (SEDDS) or microemulsions(SMEDDS). Lipids useful in the formulations of the present inventioninclude any natural or synthetic lipids including, but not limited to,sesame seed oil, olive oil, castor oil, peanut oil, fatty acid esters,glycerol esters, Labrafil®, Labrasol®, Cremophor®, Solutol®, Tween®,Capryol®, Capmul®, Captex®, and Peceol®.

The GRM composition can also contain other compatible therapeuticagents. The compounds described herein can be used in combination withone another, with other active agents known to be useful in antagonizinga glucocorticoid receptor, or with adjunctive agents that may not beeffective alone, but may contribute to the efficacy of the active agent.

Administration of a Glucocorticoid Receptor Modulator

The GRM may be a GRA, which can be a selective inhibitor of theglucocorticoid receptor. The GRM may have a steroidal backbone, and maybe, e.g., mifepristone. The GRM may have a non-steroidal backbone. Insome cases, the backbone of the GRM is a heteroaryl ketone fusedazadecalin. Additional details of GRM that can be used in the methodprovided herein are described below. The GRM may be administered once,or twice, or more times during a day. The GRM may be administered forone day; for two days; for three days; or for more days.

The GRM compounds or compositions useful in the methods disclosed hereincan be delivered by any suitable means, including oral, parenteral(e.g., intravenous injection or intramuscular injection) and topicalmethods. Transdermal administration methods, by a topical route, can beformulated as applicator sticks, solutions, suspensions, emulsions,gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

The GRM dose may be administered at any time during the day or night. Inembodiments of the methods provided herein, a GRM is administered in themorning; and may be administered in the morning prior to the morningmeal (“fasted” administration) or may be administered in the morningwithin about 30 minutes or within about one hour after the patientbegins eating the morning meal (“fed” administration). In someembodiments of the methods provided herein, at least one dose of a GRMis administered at about 11 P.M. (e.g., 2300 h) and the level of totalor free cortisol (e.g., morning plasma total cortisol, morning serumtotal cortisol, morning salivary cortisol, serum free cortisol, plasmafree cortisol, or urine free cortisol) is measured the following morningat about 8 a.m. or no later than 10 hours after GRM administration.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the compounds and compositions of the presentinvention. The unit dosage form can be a packaged preparation, thepackage containing discrete quantities of preparation, such as packetedtablets, capsules, and powders in vials or ampoules. Also, the unitdosage form can be a capsule, tablet, cachet, or lozenge itself, or itcan be the appropriate number of any of these in packaged form.

GRMs can be administered orally. For example, the GRM can beadministered as a pill, a capsule, or liquid formulation as describedherein. Alternatively, GRMs can be provided via parenteraladministration. For example, the GRM can be administered intravenously(e.g., by injection or infusion). Additional methods of administrationof the compounds described herein, and pharmaceutical compositions orformulations thereof, are described herein.

In some embodiments, the GRM is administered in one dose. In otherembodiments, the GRM is administered in more than one dose, e.g., 2doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, or more. In somecases, the doses are of an equivalent amount. In other cases, the dosesare of different amounts. The doses can increase or taper over theduration of administration. The amount will vary according to, forexample, the GRM properties and patient characteristics.

Any suitable GRM dose may be used in the methods disclosed herein. Thedose of GRM that is administered can be at least about 50 milligrams(mg) per day, about 100 mg/day, about 150 mg/day, about 200 mg/day,about 250 mg/day, about 300 mg/day, about 350 mg/day, about 400 mg/day,about 450 mg/day, about 500 mg/day, about 550 mg/day, about 600 mg/day,or more. For example, where the GRA is the HKGRM relacorilant, the HKGRMdose may be, e.g., 50 milligrams (mg) per day, 100 mg/day,150 mg/day,200 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day, 450 mg/day,500 mg/day, 550 mg/day, or 600 mg/day. For example, where the GRA ismifepristone, the GRM dose may be, e.g., 300 mg/day, or 600 mg/day, or900 mg/day, or 1200 mg/day of mifepristone. In embodiments, the GRM isadministered orally. In some embodiments, the GRM is administered in atleast one dose. In other words, the GRM can be administered in 1, 2, 3,4, 5, 6, 7, 8, 9, 10 or more doses. In embodiments, the GRM isadministered orally in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses.

The patient may be administered at least one dose of GRM in one or moredoses over, for example, a 2-48 hour period. The GRM may be administeredorally. The patient may be administered daily doses of GRM for one week,or two weeks, or three weeks, or four weeks, or two months, for threemonths, or four months, or five months, or six months, or nine months,or one year, or one and one half years, or two years, or more. In someembodiments, the GRM is administered as a single dose. In someembodiments, the GRM is administered as a single daily dose. In otherembodiments, the GRM is administered in more than one dose, e.g. 2doses, 3 doses, 4 doses, 5 doses, or more doses per day. In someembodiments, the GRM is administered over 2-48 hours, 2-36 hours, 2-24hours, 2-12 hours, 2-8 hours, 8-12 hours, 8-24 hours, 8-36 hours, 8-48hours, 9-36 hours, 9-24 hours, 9-20 hours, 9-12 hours, 12-48 hours,12-36 hours, 12-24 hours, 18-48 hours, 18-36 hours, 18-24 hours, 24-36hours, 24-48 hours, 36-48 hours, or 42-48 hours.

EXAMPLES

The following examples are offered to illustrate, but not to limit, theclaimed invention.

Treatment with relacorilant led to improvement in hyperglycemia andhypertension, generally observed within two weeks of achieving atherapeutic dose of relacorilant. In addition, significant improvementswere also observed in a number of other cortisol-related comorbiditiesas seen in TABLE 1 below:

TABLE 1 Relacorilant Treatment Leads to Improvements in Cushing'ssyndrome Patients Mean Change Endpoint Units from Baseline P-valueCoagulopathy (Factor VIII) % −18.94 <0.03 Coagulopathy (Platelets) 10⁹/L−68.82 <0.0001 Coagulopathy (APTT) Seconds +1.45 <0.05 Inflammation(eosinophils) 10⁹/L 0.05 <0.01 Serum Osteocalcin μg/L 3.00 <0.01In TABLE 1 above, the P-value is a Wilcoxon Signed Rank P-value; meanchange from baseline indicates the mean change from the initial(baseline) values to the last-observed values; Factor VIII values arereported as percent of normal values; platelet counts and eosinophilcounts are reported as numbers of cells per liter; APTT indicatesactivated partial thromboplastin time, measured in seconds; and serumosteocalcin measures levels of the vitamin K-related hormone osteocalcinoutside of bone.

FIG. 1A shows levels of the coagulation factors over time in Cushing'ssyndrome patients treated with relacorilant. Relacorilant wasadministered to the patients once per day for four months. Two groups ofCushing's syndrome patients received relacorilant. Group 1 received 100milligrams per day (mg/day) which, if tolerated, was raised to 200mg/day for the 16 weeks of the study. Group 2 received relacorilantdoses according to the following schedule: the starting doses were 250milligrams (mg) per day of relacorilant for four weeks, followed by 300mg/day relacorilant for the next four weeks, followed by 350 mg/dayrelacorilant for a further four weeks, and then 400 mg relacorilant foranother four weeks. (Some patients did not tolerate the higher doses,and remained on a lower dose for the duration of the study, or ended thestudy prior to 16 weeks.)

In FIG. 1A, normalized levels of Factor VIII (darker column at the leftof each pair of columns) and von Willebrand Factor (lighter column atthe right of each pair of columns (Vwf)) are shown (as % of the levelsfound in normal subjects). Factor VIII and von Willebrand Factor atbaseline, prior to relacorilant administration (left-most pair ofcolumns); after four weeks of relacorilant treatment (middle pair ofcolumns); and after 3 or 4 months of relacorilant treatment (right-mostpair of columns). Factor VIII levels are reduced, as compared tobaseline, at week four and after 3 or 4 months of relacorilanttreatment. Von Willebrand factor levels initially rise somewhat (at fourweeks), and then return to baseline levels after 3 or 4 months ofrelacorilant treatment.

FIG. 2A shows activated prothrombin time (APTT) measured in 12 Cushing'ssyndrome patients before and after receiving relacorilant. The APTT ofGroup 2 patients receiving relacorilant was measured at baseline (beforerelacorilant administration) and after 16 weeks (or following the lastrelacorilant administration for those patients who did receive the full16 weeks of relacorilant administration). As shown in FIG. 2A, APTTincreased significantly in this group following relacorilantadministration (p-value: 0.014). Increased APTT indicates an increase inthe time for blood coagulation; that is, a reduction inhypercoagulation. Thus, these results indicate that, for patientsinitially suffering from hypercoagulopathy (i.e., as in these Cushing'spatients), the hypercagulopathy was reduced, and the risk of clottingdisorders associated with hypercoagulopathy, such as DVT, PE, and VTE,are reduced.

Improvement/normalization of abnormally elevated coagulation factorscaused by excess cortisol activity was observed as early as after onemonth of treatment with relacorilant. This is in contrast to what isobserved after curative surgery for pituitary Cushing syndrome caseswhere coagulation factors start to decrease 3 months post-surgery andoften remain elevated for at least 6 months post-surgery (Trementino etal., Neuroendocrinology 92 Suppl 1:55-59 (2010). Considering the highrisk of thrombotic events in patients with active Cushing syndrome aswell as following curative surgery, relacorilant might even be an optionfor pre-operative coagulation control of patients at high risk ofperi-and post-operative thrombotic events.

FIG. 2B shows the effects of relacorilant on coagulation factors(thrombin-antithrombin). The coagulation profile of the Cushing'spatients treated with relacorilant was improved compared to baseline.Coagulation factors, and risk of disorders such as DVT, PE, and VTE,change after surgical treatment for Cushing's syndrome (e.g., afterresection of a pituitary tumor in a patient suffering from Cushing'sDisease). Factor VIII levels and von Willebrand Factor levels inCushing's patients undergoing surgery were elevated before surgery(about 150% to 200% of normal), and increased one month after surgery.It took up to six months or more for these levels to be reduced to thosethat obtained prior to surgery; Factor VIII and von Willebrand Factorlevels were improved at 12 months after surgery, to levels below about125% of normal (Casonato, et al. Blood Coagulation and Fibrinolysis10(3):145-151 (1999)).

In contrast, as shown in FIGS. 1A, 1B, and 1C, neither Factor VIII orvon Willebrand's Factor increased greatly with relacorilantadministration. Moreover, Factor VIII levels declined after only 3 or 4months of relacorilant treatment. In addition, as shown in FIG. 2 , APTTmeasurements increased in Cushing's patients receiving relacorilant,indicating reduced risk of coagulation and reduced risk of DVT, PE, andVTE. These results show that relacorilant treatment improves thecoagulation profile of Cushing's patients. These results further suggestthat relacorilant treatment of Cushing's patients provides a bettercoagulation factor profile, earlier after treatment, than does surgery.

FIG. 3 shows C-Reactive protein levels over time in the Cushing'ssyndrome patients treated with relacorilant. C-Reactive protein level iscorrelated with the level of inflammation in a patient. C-Reactiveprotein levels initially rise somewhat (at four weeks), and then returnto baseline levels after 3 or 4 months of relacorilant treatment. Thesechanges in C-Reactive protein levels are similar to those observed forVon Willebrand factor levels as well. Thus, the changes in theinflammation marker C-Reactive protein are similar to those seen forcoagulation factors.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, one of skill in the art will appreciate that certainchanges and modifications may be practiced within the scope of theappended claims. In addition, each patent, patent publication, andreference cited herein is incorporated by reference in its entirety tothe same extent as if each patent, patent publication, and reference wasindividually incorporated by reference.

We claim:
 1. A method of treating hypercoagulopathy in a Cushing'ssyndrome patient, the method comprising: Administering an effectiveamount of a glucocorticoid receptor modulator (GRM) to said patient, andadministering an effective amount of an anticoagulation therapy, Wherebysaid hypercoagulopathy in said Cushing's syndrome patient is treated. 2.The method of claim 1, wherein the GRM is administered orally.
 3. Themethod of claim 1, wherein the Cushing's syndrome patient suffers fromCushing's Disease.
 4. The method of claim 1, wherein the GRM is aglucocorticoid receptor antagonist (GRA).
 5. The method of claim 1,wherein the GRM is mifepristone.
 6. The method of claim 1, wherein theGRM is a non-steroidal GRM having a heteroaryl ketone fused azadecalinbackbone.
 7. The method of claim 6, wherein the GRM is selected fromrelacorilant, CORT122928, and CORT113176.
 8. The method of claim 6,wherein the GRM is relacorilant.
 9. The method of claim 1, wherein saideffective amount of said GRM is a daily amount selected from 50milligrams (mg), 100 mg. 150 mg. 200 mg, 250 mg, 300 mg, 350 mg, and 400mg.
 10. The method of claim 9, wherein said effective amount of said GRMis a once daily amount of said GRM.
 11. A method of treating deep veinthrombosis (DVT), pulmonary embolism (PE), or venous thromboembolism(VTE) in a Cushing's syndrome patient, the method comprising:Administering an effective amount of a glucocorticoid receptor modulator(GRM) to said patient and administering an effective amount of ananticoagulation therapy, Whereby said DVT, PE, or VTE in said Cushing'ssyndrome patient is treated.
 12. The method of claim 11, wherein the GRMis administered orally.
 13. The method of claim 11, wherein the patientsuffers from Cushing's syndrome.
 14. The method of claim 11, wherein theGRM is a glucocorticoid receptor antagonist (GRA).
 15. The method ofclaim 11, wherein the GRM is mifepristone.
 16. The method of claim 11,wherein the GRM is a non-steroidal GRM having a heteroaryl ketone fusedazadecalin backbone.
 17. The method of claim 16, wherein the GRM isselected from relacorilant, CORT122928, and CORT113176.
 18. The methodof claim 16, wherein the GRM is relacorilant.
 19. The method of claim11, wherein said effective amount of said GRM is a daily amount selectedfrom 50 milligrams (mg), 100 mg. 150 mg. 200 mg, 250 mg, 300 mg, 350 mg,and 400 mg.
 20. The method of claim 19, wherein said effective amount ofsaid GRM is a once daily amount of said GRM.